Human Desmocollin 3-Specific IgG Antibodies Are Pathogenic in a Humanized HLA Class II Transgenic Mouse Model of Pemphigus
Human Desmocollin 3-Specific IgG Antibodies Are Pathogenic in a Humanized HLA Class II Transgenic Mouse Model of Pemphigus
复制标题
DOI：
10.1016/j.jid.2021.06.017
复制
发表时间：
2022-02-18
影响因子：
6.5
通讯作者：
Eming, Ruediger
中科院分区：
文献类型：
--
作者：
Hudemann, Christoph;Maglie, Roberto;Eming, Ruediger
天疱疮是一种潜在的致死性自身免疫性大疱性皮肤病，与抗粘粒蛋白（DSG） 3和DSG1的IgG自身抗体有关。值得注意的是，一部分天疱疮患者在缺乏抗dsg IgG的情况下表现出相似的临床表型，这表明血清IgG与DSG1或DSG3以外的桥粒组分反应。我们和其他人之前已经表明，这类患者具有抗桥粒蛋白3 （DSC3）的血清IgG自身抗体，桥粒蛋白3是桥粒的一种成分，可诱导角质细胞体外粘附丧失。此外，DSC3型小鼠表现出严重的粘膜起泡表型，这是天疱疮的高度特征。这些发现促使我们在转HLA-DRB1*04:02的人源化小鼠中研究抗人DSC3 IgG的诱导和调控，HLA-DRB1*04:02是天疱疮中高度流行的单倍型。我们发现免疫小鼠血清中的IgG通过激活p38 MAPKs和EGFR诱导棘层溶解。经重组人DSC3免疫的小鼠将被动IgG转移到新生儿体内不会导致表皮内黏着丧失，这可能是由于人和小鼠DSC3缺乏同源性。人DSC3在体外刺激DSC3免疫小鼠脾细胞，可引起显著的增殖性ifn - γ和IL-4 t细胞反应，该反应受HLA-DR/HLA-DQ限制。这些发现提示病原性抗DSC3 IgG的诱导与识别DSC3的DSC3特异性T细胞与HLA- DRB1*04:02相关。
Pemphigus is a potentially lethal autoimmune bullous skin disorder, which is associated with IgG autoantibodies against desmoglein (DSG) 3 and DSG1. Notably, a subset of patients with pemphigus presents with a similar clinical phenotype in the absence of anti-DSG IgG, suggesting the presence of serum IgG reactive with desmosomal components other than DSG1 or DSG3. We and others have previously shown that such patients have serum IgG autoantibodies against desmocollin 3 (DSC3), a component of desmosomes, which induce loss of keratinocyte adhesion ex vivo. Moreover, DSC3 hypomorphic mice show a severe blistering phenotype of the mucous membrane, which is highly characteristic of pemphigus. These findings prompted us to study the induction and regulation of anti-human DSC3 IgG in humanized mice transgenic for HLA-DRB1*04:02, which is a highly prevalent haplotype in pemphigus. We show that IgG from sera of immunized mice induces acantholysis in a dispase-based keratinocyte dissociation assay through the activation of p38 MAPKs and EGFR. Passive IgG transfer from mice immunized with recombinant human DSC3 into neonates did not induce intraepidermal loss of adhesion presumably owing to the lack of homology between human and mouse DSC3. Ex vivo stimulation of splenocytes from DSC3-immunized mice with human DSC3 leads to a significant proliferative IFN-gamma and IL-4 T-cell response, which is restricted by HLA-DR/HLA-DQ. These findings suggest that the induction of pathogenic anti-DSC3 IgG is associated with DSC3-specific T cells that recognize DSC3 in association with HLA- DRB1*04:02.